26 research outputs found
Integrative genomics and transcriptomics analysis of human embryonic and induced pluripotent stem cells
Identification, Replication, and Functional Fine-Mapping of Expression Quantitative Trait Loci in Primary Human Liver Tissue
The discovery of expression quantitative trait loci (âeQTLsâ) can
help to unravel genetic contributions to complex traits. We identified genetic
determinants of human liver gene expression variation using two independent
collections of primary tissue profiled with Agilent
(nâ=â206) and Illumina (nâ=â60)
expression arrays and Illumina SNP genotyping (550K), and we also incorporated
data from a published study (nâ=â266). We found that
âŒ30% of SNP-expression correlations in one study failed to replicate
in either of the others, even at thresholds yielding high reproducibility in
simulations, and we quantified numerous factors affecting reproducibility. Our
data suggest that drug exposure, clinical descriptors, and unknown factors
associated with tissue ascertainment and analysis have substantial effects on
gene expression and that controlling for hidden confounding variables
significantly increases replication rate. Furthermore, we found that
reproducible eQTL SNPs were heavily enriched near gene starts and ends, and
subsequently resequenced the promoters and 3âČUTRs for 14 genes and tested
the identified haplotypes using luciferase assays. For three genes, significant
haplotype-specific in vitro functional differences correlated
directly with expression levels, suggesting that many bona fide
eQTLs result from functional variants that can be mechanistically isolated in a
high-throughput fashion. Finally, given our study design, we were able to
discover and validate hundreds of liver eQTLs. Many of these relate directly to
complex traits for which liver-specific analyses are likely to be relevant, and
we identified dozens of potential connections with disease-associated loci.
These included previously characterized eQTL contributors to diabetes, drug
response, and lipid levels, and they suggest novel candidates such as a role for
NOD2 expression in leprosy risk and
C2orf43 in prostate cancer. In general, the work presented
here will be valuable for future efforts to precisely identify and functionally
characterize genetic contributions to a variety of complex traits
Extending the duration of hypothermia does not further improve white matter protection after ischemia in term-equivalent fetal sheep
Skin autofluorescence predicts incident type 2 diabetes, cardiovascular disease and mortality in the general population
Advanced glycation end products, aortic stiffness, and wave reflection in peritoneal dialysis as compared to hemodialysis
A Network Analysis of the Links Between Chronic Pain Symptoms and Affective Disorder Symptoms
Phylogeny and typification of Madurella mycetomatis, with a comparison of other agents of eumycetoma. Phylogenie und Typisierung von Madurella mycetomatis im Vergleich mit anderen Erregern von Eumyzetomata
Association of reperfusion with brain edema in patients with acute ischemic stroke: A secondary analysis of the MR CLEAN Trial
IMPORTANCE:
It is uncertain whether therapeutic reperfusion with endovascular treatment yields more or less brain edema. OBJECTIVE To elucidate the association between reperfusion and brain edema. The secondary objectives were to evaluate whether brain edema could partially be responsible for worse outcomes in patients with later reperfusion or lower Alberta Stroke Program Early Computed Tomography Score.
DESIGN, SETTING, AND PARTICIPANTS:
This was a post hoc analysis of the Multicenter Randomized Clinical Trial of Endovascular Treatment for Acute Ischemic Stroke in the Netherlands (MR CLEAN), which was a prospective, randomized, multicenter clinical trial of endovascular treatment compared with conventional care of patients with acute anterior circulation ischemic stroke. Of 502 patients enrolled from December 2010 to June 2014, 2 patients declined to participate. Additionally, exclusion criteria were absence of follow-up imaging or presence of parenchymal hematoma, resulting in 462 patients included in this study. Brain edema was assessed retrospectively, from December 10, 2016, to July 24, 2017, by measuring midline shift (MLS) in all available follow-up scans. Observers were blinded to clinical data.
MAIN OUTCOMES AND MEASURES:
Midline shift was assessed as present or absent and as a continuous variable. Reperfusion status was assessed by the modified thrombolysis in cerebral infarction score in the endovascular treatment arm. The modified arterial occlusive lesion score was used to evaluate the recanalization status in both arms. The modified Rankin scale score at 90 days was used for functional outcome. RESULTS Of 462 patients, the mean (SD) age was65 (11) years, and 41.8% (n = 193) were women. Successful reperfusion and recanalization were associated with a reduced likelihood of having MLS (adjusted common odds ratio, 0.25; 95% CI, 0.12-0.53; P < .001 and adjusted common odds ratio, 0.34; 95% CI, 0.21-0.55; P < .001, respectively). Midline shift was partially responsible for worse modified Rankin scale scores in patients without reperfusion or recanalization (MLS changed the logistic regression coefficients by 30.3% and 12.6%, respectively). In patients with delayed reperfusion or lower Alberta Stroke Program Early Computed Tomography Score, MLS mediated part of the worse modified Rankin scale scores, corresponding to a change in the regression coefficient of 33.3% and 64.2%, respectively.
CONCLUSIONS AND RELEVANCE:
Successful reperfusion was associated with reduced MLS. This study identifies an additional benefit of reperfusion in relation to edema, as well as rescuing ischemic brain tissue at risk for infarction